This is a resubmission of an application for a new R15 AREA (Academic Research Enhancement Award) grant. The original application was reviewed in October 2005. A consistent literature has demonstrated the presence of hippocampal abnormalities in neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease (AD), and, in both disorders, changes in hippocampal function and structure have been linked to memory impairment. But to our knowledge, an animal model of reduced hippocampal volume has not been used to assay new treatments for memory deficits. The development and use of such a model is important since existing animal models of memory loss involving systemic decreases in acetylcholine or glutamate function may not adequately emulate the pathophysiology of memory deficits caused by hippocampal dysfunction. The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies performed since the original application that thioperamide, a highly selective antagonist at histamine H3 receptors, clearly alleviates injury-induced deficits in spatial working memory. As a result of this data, we hypothesize that thioperamide and related H3 antagonists will improve spatial working memory in rats with adult and neonatal excitotoxic injury to the hippocampus. The specific aims of this proposal are intended to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury, 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury, & 3) Can H3 antagonists alleviate changes in spatial working memory, prepulse inhibition, and locomotor activity in rats with neonatal-onset hippocampal injury? The results of these studies should improve our understanding of memory deficits specifically linked to hippocampal dysfunction and suggest new treatment strategies for such deficits in neuropsychiatric disorders. The funding of this application will also expand student research in behavioral neuroscience and psychopharmacology and better enable students from Kentucky, a state traditionally underrepresented in biomedical sciences, to successfully advance into biomedical graduate programs. Memory loss associated with clinical disorders, such as Alzheimer's Disease or schizophrenia, has been linked to reductions in the size of specific brain regions. The proposed studies are designed to study memory in laboratory rats with similar changes in regional brain size and to identify new treatments for the memory impairment associated with these size changes. The results may shed light on new directions in the treatment of memory disorders, and the proposed work will also enhance education in biomedical research among college undergraduates in Kentucky. [unreadable] [unreadable] [unreadable]